title: Rosiglitazone regulates c-reactive protein-induced inflammatory responses via glucocorticoid receptor-mediated inhibition of p38 mitogen-activated protein kinase-toll-like receptor 4 signal pathway in vascular smooth muscle cells.
abstract: C-reactive protein (CRP) activates toll-like receptor 4 (TLR4) to initiate inflammatory response involved in the pathogenesis of atherosclerosis through mitogen-activated protein kinase (MAPK) signal pathways. Rosiglitazone, a synthetic peroxisome proliferator-activated receptor γ (PPARγ) agonist, is considered to be an important inhibitor of the inflammatory response. The present study was to explore the effect of rosiglitazone on the CRP-induced inflammatory responses and the related signal pathway in vascular smooth muscle cells (VSMCs). The results showed that rosiglitazone reduced the expressions of proinflammatory cytokines, such as vascular endothelial growth factor-A and inducible nitric oxide synthase, and enhanced the expression or activation of anti-inflammatory transcription factors including PPARγ and glucocorticoid receptor (GR) in VSMCs in response to CRP. The further investigations indicated that rosiglitazone inhibited CRP-induced TLR4 expression and p38 MAPK phosphorylation in VSMCs, and TLR4 knockdown potentiated the inhibitory effects of rosiglitazone on vascular endothelial growth factor-A and inducible nitric oxide synthase expressions. In addition, GR antagonist RU486 but not PPARγ inhibitor GW9662 remarkably weakened the inhibitory effects of rosiglitazone on CRP-induced TLR4 expression and p38 phosphorylation in VSMCs. But GW9662 did not affect rosiglitazone-induced GR phosphorylation. These suggest that rosiglitazone exerts its anti-inflammatory effect through activating GR and subsequently inhibiting p38 MAPK-TLR4 signaling pathway in CRP-stimulated VSMCs.
authors.affiliation: Department of Pharmacology, the Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Jun-Tian
authors.initials: JT
authors.lastname: Liu
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Ji
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Lu
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D018929:Cell Culture Techniques; D004731:Endotoxins / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D045162:Thiazolidinediones / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D004731:Endotoxins; D007004:Hypoglycemic Agents; D011965:Receptors, Glucocorticoid; C495345:TLR4 protein, human; D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; D000077154:Rosiglitazone; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases